Orodispersible dosage unit containing an estetrol component

ABSTRACT

The invention provides an orodispersible solid pharmaceutical dosage unit having a weight between 30 and 1,000 mg, said dosage unit consisting of: 0.1-25 wt. % of estetrol particles containing at least 80 wt. % of an estetrol component selected from estetrol, estetrol esters and combinations thereof; and 75-99.9 wt. % of one or more pharmaceutically acceptable ingredients; the solid dosage unit comprising at least 100 μg of the estetrol component; and wherein the solid dosage unit can be obtained by a process comprising wet granulation of estetrol particles having a volume weighted average particle size of 2 μm to 50 μm. The solid dosage unit is easy to manufacture and perfectly suited for sublingual, buccal or sublabial administration.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the U.S. National Stage of International ApplicationPCT/EP2016/064065, filed Jun. 17, 2016, which claims priority fromEuropean Patent Application No. 15172767.4, filed Jun. 18, 2015.

TECHNICAL FIELD OF THE INVENTION

The present invention provides an orodispersible solid pharmaceuticaldosage unit having a weight of 30-1,000 mg and containing at least 0.1mg of an estetrol component selected from estetrol, estetrol esters andcombinations thereof. This solid dosage unit consists of:

-   -   0.1-25 wt. % of estetrol particles containing at least 80 wt. %        of the estetrol component; and    -   75-99.9 wt. % of one or more pharmaceutically acceptable        ingredients.

The invention also provides a process of preparing the aforementionedsolid dosage unit.

Furthermore, the invention relates to the use of the solid dosage unitin medical treatment, female hormone replacement therapy and femalecontraception, said use comprising sublingual, buccal or sublabialadministration of the solid dosage unit.

BACKGROUND OF THE INVENTION

Estetrol is a human steroid, produced by the fetal liver duringpregnancy only. This natural hormone was discovered in urine of pregnantwomen by Diczfalusy and coworkers in 1965. Estetrol has the structure ofan estrogenic steroid with four hydroxyl groups. Estetrol is synthesizedin the fetal liver from estradiol and estriol by the two enzymes 15α-and 16α-hydroxylase. After birth the neonatal liver rapidly loses itscapacity to synthesize estetrol because these two enzymes are no longerexpressed.

Estetrol reaches the maternal circulation through the placenta and wasalready detected at nine weeks of pregnancy in maternal urine. Duringthe second trimester of pregnancy high levels were found in maternalplasma, with steadily rising concentrations of unconjugated estetrol toabout 1 ng/mL (>3 nmol/L) towards the end of pregnancy. So far thephysiological function of estetrol is unknown. The possible use ofestetrol as a marker for fetal well-being has been studied quiteextensively. However, due to the large intra- and inter-individualvariation of maternal estetrol plasma levels during pregnancy thisappeared not to be feasible.

Since 2001 estetrol has been studied extensively. In humans estetrol wasshown to have a high and dose-proportional oral bioavailability and along terminal elimination half-life of about 28 hours. Results from invitro studies showed that estetrol binds highly selective to theestrogen receptors with preference for the ERα form of the receptor,unlike the estrogens ethinyl estradiol and 17β-estradiol. Also incontrast with ethinyl estradiol and especially with 17β-estradiol,estetrol does not bind to sex hormone binding globulin (SHBG) and doesnot stimulate the production of SHBG in vitro.

The properties of estetrol have also been investigated in a series ofpredictive, well validated pharmacological in vivo rat models. In thesemodels, estetrol exhibited estrogenic effects on the vagina, the uterus(both myometrium and endometrium), body weight, bone mass, bonestrength, hot flushes and on ovulation (inhibition). All these effectsof estetrol were dose-dependent with maximum effects at comparable doselevels. Surprisingly, estetrol prevented tumour development in a DMBAmammary tumour model to an extent and at a dose level similar to theanti-estrogen tamoxifen and to ovariectomy. This anti-estrogenic effectof estetrol in the presence of 17β-estradiol has also been observed inin vitro studies using human breast cancer cells.

Buccal, sublingual or sublabial administration of estetrol is mentionedin a number of patent applications, including WO 2002/094275, WO2002/094276, WO 2002/094278 and WO 2003/018026. Estetrol containingdosage units for buccal, sublingual or sublabial administration are notdescribed in these publications.

WO 2010/033832 describes an oral dosage form comprising an estriolcompound and a pharmaceutically acceptable matrix material, wherein theoral dosage form releases at least about 90% of the estriol compound ina time of less than about 300 seconds when contacted with saliva of thebuccal and/or sublingual cavity.

US 2007/286829 describes an orally administered solid dosage formcapable of delivering ethinyl estradiol with improved bioavailability,said solid dosage form comprising (i) about 0.5 μg to about 50 μg ofethinyl estradiol and (ii) an oral dissolution enhancing carrier thatprovides for at least 15% absorption of the ethinyl estradiol throughthe oral mucosa when said solid dosage form is orally administered tothe patient with 2 ounces of water or less.

U.S. Pat. No. 6,117,446 describes a buccal dosage unit for administeringa combination of steroidal active agents, comprising a compressed tabletof a bioerodible polymeric carrier and therapeutically effective amountsof an androgenic agent selected from testosterone and pharmacologicallyacceptable esters thereof, a progestin and an estrogen. The examplesdescribe buccal dosage units that were prepared by thoroughly mixing thefollowing components: estrogen, progestogen, androgen, polyethyleneoxide, carbomer and magnesium stearate. Next, the mixture was granulatedby means of fluid bed granulation and the granulate so obtained waspressed into tablets.

Oral dosage units containing estetrol have been described in severalpatent publications.

WO 2002/094276 describes a pharmaceutical composition for use in amethod of hormone replacement therapy, which method comprisesadministering to a person in need of such a therapy an effective amountof estetrol, said composition containing virtually no progestogen oranti-progestin. WO 2002/094276 describes the preparation of estetroltablets having a weight of 185 mg, containing 1.5 mg estetrol, on thebasis of the following formulation:

mg Estetrol 1.5 Polyvinylpyrrolidone (Kollidon 25 ® ex BASF) 12.5Lactose 135.795 Microcrystalline cellulose (Avicel PH 101 ®) 26.25Glyceryl palmitostearate (Precirol ®) 2.775 Anhydrous colloidal silica(Aerosil 200 ®) 1.0 Crospovidone (Polyplasdone XL ®) 4.0 Coloring agent0.18

WO 2002/094275 describes the use of an estetrol in a method ofincreasing libido in a woman, said method comprising administering tosaid woman an effective amount of estetrol. Oral administration ismentioned as a suitable mode of administration. This patent applicationdescribes the same estetrol tablet as WO 2002/094276.

WO 2002/094279 describes the use of estetrol in a method ofcontraception in mammalian females, which method comprises the oraladministration of said estrogenic component and a progestogeniccomponent to a female of childbearing capability in an effective amountto inhibit ovulation. The following formulation for a 185 mg estetroltablet is described in this international patent application.

mg Estetrol 1.5 Levonorgestrel 0.15 Polyvinylpyrrolidone (Kollidon 25 ®ex BASF) 13.5 Lactose 135.645 Microcrystalline cellulose (Avicel PH101 ®) 26.25 Glyceryl palmitostearate (Precirol ®) 2.775 Anhydrouscolloidal silica (Aerosil 200 ®) 1.0 Crospovidone (Polyplasdone XL ®)4.0 Coloring agent 0.18

WO 2003/041718 describes the use of estetrol in a method of hormonereplacement in mammals, which method comprises the oral administrationof estetrol and a progestogenic component to a mammal in an effectiveamount to prevent or treat symptoms of hypoestrogenism. This patentapplication describes the same estetrol tablet as WO 2002/094279.

WO 2007/081206 describes the use of estetrol in a method of treating anacute vascular disorder in a mammal, said method comprising orallyadministering to said mammal, upon demand, an effective amount of theestetrol to the mammal. This patent application describes thepreparation of hard gelatine capsules, containing 100 mg estetrol and 25mg sildenafil citrate per capsule.

WO 2008/156365 describes the use of estetrol in the treatment ofMeconium Aspiration Syndrome (MAS) in a newborn infant, said treatmentcomprising administering an effective amount of estrogen to said newborninfant within 7 days after birth. The international patent applicationdescribes a suppository for use in newborn infants comprising at least 1μg of estrogen, said suppository further being characterized by amaximum diameter of less than 10 mm and a weight of less than 0.5 g. Theexcipient contained in the suppository may be based on lipid materialthat melts at body temperature or it may be based on a hydrophiliccomponent that dissolves or disintegrates when it comes into contactwith water.

SUMMARY OF THE INVENTION

The present invention provides an orodispersible solid pharmaceuticaldosage unit containing an estetrol component. The dosage unit rapidlyreleases the estetrol in aqueous environment. The solid dosage unit iseasy to manufacture and perfectly suited for sublingual, buccal orsublabial administration. Sublingual, buccal and sublabialadministration each offer the advantages that the estetrol componentdoes not have to pass through the digestive system and avoids first-passliver exposure. Furthermore, these modes of administration provide arapid onset of action.

The solid dosage unit according to the present invention has a weightbetween 30 and 1,000 mg; contains at least 100 μg of an estetrolcomponent selected from estetrol, estetrol esters and combinationsthereof; and consists of:

-   -   0.1-25 wt. % of estetrol particles containing at least 80 wt. %        of the estetrol component; and    -   75-99.9 wt. % of one or more pharmaceutically acceptable        ingredients.

This solid dosage is obtainable by a process comprising:

-   -   providing estetrol particles containing at least 80 wt. % of the        estetrol component and having a volume median diameter of 2 μm        to 50 μm;    -   mixing the estetrol particles with one or more granulation        excipients to produce a granulation mixture;    -   mixing the granulation mixture with a granulation liquid to        produce estetrol-containing granules, said granulation liquid        containing at least 60 wt. % of liquid solvent;    -   removing liquid solvent from the estetrol-containing granules to        produce dry estetrol-containing granules;    -   optionally mixing the dry granules with one or more tabletting        excipients; and    -   forming the dry granules or the mixture of the dry granules and        the one or more tabletting excipients into a solid dosage unit.

Rapid and complete dissolution of the estetrol component into saliva isessential for efficient delivery of the component via sublingual, buccalor sublabial administration of the solid dosage unit. The inventors haveunexpectedly found that the estetrol component is rapidly released anddispersed into saliva and absorbed through the mucosal lining of theoral cavity if it is present in the solid dosage unit in the form ofvery small particles.

The invention also provides a process of preparing the aforementionedsolid dosage unit, said process comprising the steps of:

-   -   providing estetrol particles containing at least 80 wt. % of an        estetrol component selected from estetrol, estetrol esters and        combinations thereof and having a volume median diameter of 2 μm        to 50 μm;    -   mixing the estetrol particles with one or more granulation        excipients to produce a granulation mixture;    -   mixing the granulation mixture with a granulation liquid to        produce estetrol-containing granules, said granulation liquid        containing at least 60 wt. % of liquid solvent;    -   removing liquid solvent from the estetrol-containing granules to        produce dry estetrol-containing granules;    -   optionally mixing the dry granules with one or more        pharmaceutically acceptable excipients; and    -   forming the dry granules or the mixture of the dry granules and        the one or more tabletting excipients into a solid dosage unit

The production of the estetrol-containing granules in this process maysuitably be carried out, for instance, in a high shear granulator, a lowshear granulator or a fluidized bed granulator.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 illustrates the manufacturing process flow chart used in Example4.

DETAILED DESCRIPTION OF THE INVENTION

A first aspect of the invention relates to an orodispersible solidpharmaceutical dosage unit having a weight between 30 and 1,000 mg, saiddosage unit consisting of:

-   -   0.1-25 wt. % of estetrol particles containing at least 80 wt. %        of an estetrol component selected from estetrol, estetrol esters        and combinations thereof; and    -   75-99.9 wt. % of one or more pharmaceutically acceptable        ingredients;        the solid dosage unit comprising at least 100 μg of the estetrol        component;        wherein the solid dosage unit can be obtained by a process        comprising:    -   providing estetrol particles containing at least 80 wt. % of the        estetrol component and having a volume median diameter of 2 μm        to 50 μm;    -   mixing the estetrol particles with one or more granulation        excipients to produce a granulation mixture;    -   mixing the granulation mixture with a granulation liquid to        produce estetrol-containing granules, said granulation liquid        containing at least 60 wt. % of liquid solvent;    -   removing liquid solvent from the estetrol-containing granules to        produce dry estetrol-containing granules;    -   optionally mixing the dry granules with one or more tabletting        excipients; and    -   forming the dry granules or the mixture of the dry granules and        the one or more tabletting excipients into a solid dosage unit.

The term ‘estetrol’ as used herein refers to 1,3,5(10)-estratrien-3,15α,16α,17β-tetrol or 15α-hydroxyestriol as well ashydrates of estetrol, e.g. estetrol monohydrate.

The term ‘orodispersible dosage unit’ as used herein refers to a dosageunit that is designed to rapidly disintegrate in the oral cavity when itcomes into contact with saliva and to disperse the estetrol componentinto the saliva so it may be absorbed through the mucosal lining of theoral cavity.

The terms ‘pharmaceutically acceptable ingredients’ as used hereininclude both pharmaceutically acceptable excipients and pharmaceuticallyactive ingredients other than the estetrol component, as further definedbelow.

The term ‘sublingual’ as used herein refers to the pharmacological routeof administration by which the estetrol component diffuses into theblood through tissues under the tongue.

The term ‘buccal’ as used herein refers to the pharmacological route ofadministration by which the estetrol component diffuses into the bloodthrough tissues of the buccal vestibule, the area inside the mouthbetween the lining of cheek (the buccal mucosa) and the teeth/gums.

The term ‘sublabial’ as used herein refers to the pharmacological routeof administration by which the estetrol component is placed between thelip and the gingiva.

The term “granulation” as used herein, unless indicated otherwise,relates to a process in which primary powder particles are made toadhere to form larger, multiparticle entities called “granules”.

The term ‘tabletting excipient’ as used herein refers to apharmaceutically acceptable excipient that can be used in themanufacture of solid dosage units such as tablets.

Unless indicated otherwise, all percentages mentioned herein arepercentages by weight.

Examples of solid dosage units encompassed by the present inventioninclude tablets, dragees, lozenges and films. In accordance with apreferred embodiment, the dosage unit is a tablet, most preferably acompressed tablet.

The solid dosage unit typically has a weight between 40 and 500 mg, morepreferably between 50 and 300 mg, and most preferably between 70 and 150mg.

The solid dosage unit preferably comprises at least 1 wt. %, morepreferably 2-25 wt. % and most preferably 2.2-15 wt. % of the estetrolcomponent.

The amount of the estetrol component contained in the solid dosage unitpreferably lies within the range of 0.3-100 mg, more preferably of0.5-40 mg and most preferably of 1-20 mg.

The estetrol component of the present invention preferably is selectedfrom the group consisting of estetrol, esters of estetrol wherein thehydrogen atom of at least one of the hydroxyl groups has beensubstituted by an acyl radical of a hydrocarbon carboxylic, sulfonicacid or sulfamic acid of 1-25 carbon atoms; and combinations thereof.Even more preferably, the estetrol component is estetrol (includingestetrol hydrates). Most preferably, the estetrol component contained inthe dosage unit is estetrol monohydrate.

The particle size of the estetrol particles in the solid dosage unitshould be adequate for achieving sufficient absorption of the estetrolcomponent after sublingual, buccal or sublabial administration. Theestetrol particles within the solid dosage unit and (independently) theestetrol particles used in the preparation of the solid dosage unitpreferably have a volume median diameter in the range of 3 μm to 35 μm,more preferably in the range of 4 μm to 25 μm and most preferably in therange of 5 μm to 15 μm.

The estetrol particles within the solid dosage unit and (independently)the estetrol particles used in the preparation of the solid dosage unitpreferably contain not more than a limited amount of particles with aparticle size in excess of 60 μm. Preferably, not more than 10 vol. % ofmore than 60 μm (D₉₀), more preferably not more than 5 vol. % of theestetrol particles have a particle size of more than 60 μm (D₉₅). Evenmore preferably, not more than 10 vol. % of more than 40 μm (D₉₀), morepreferably not more than 5 vol. % of the estetrol particles have aparticle size of more than 40 μm (D₉₅).

The particles size distribution of the estetrol particles, and of otherparticulate materials used in the present process, may suitably bedetermined by means of laser diffraction. The particle size distributionof the estetrol particles within the solid dosage unit can suitably bedetermined using spectroscopic techniques, e.g. Raman mapping.

The solid dosage unit of the present invention offers the advantage thatthe estetrol component is rapidly released when the dosage unit isintroduced into the oral cavity and comes into contact with saliva. Therate of release of the estetrol component from the dosage unit cansuitably be determined using the dissolution test described in theExamples, or a disintegration test according to Ph. Eur. 2.9.1(“Disintegration of tablets and capsules”) and USP <701>(“Disintegration”), also described in the Examples. The solid dosageunit of the present invention, when subjected to the aforementioneddissolution test, typically releases at least 50%, more preferably atleast 70% and most preferably at least 80% of the estetrol componentafter 5 minutes. The solid dosage unit of the present invention, whensubjected to the aforementioned disintegration test, typicallydisintegrates within less than 5 minutes, more preferably within lessthan 2 minutes, still more preferably within less than 1.5 minutes,still more preferably within less than 1 minute, still more preferablywithin less than 45 seconds, and most preferably within less than 30seconds.

The estetrol particles employed in the solid dosage unit and in thepresent process preferably contain at least 90 wt. % of the estetrolcomponent, more preferably at least 95 wt. % of the estetrol componentand most preferably at least 99 wt. % of the estetrol component. Besidesthe estetrol component, the estetrol particles can suitably containpharmaceutically acceptable excipients that aid dispersion of the dosageunit and dissolution and absorption of the estetrol component. Examplesof such excipients include tensioactive agents, cosolvents, absorptionenhancer, superdisintegrants and buffering agents.

The estetrol particles typically represent between 0.5-20 wt. % of thedosage unit. More preferably, the estetrol particles represent 1-18 wt.%, most preferably 5-15 wt. % of the dosage unit.

The solid dosage unit of the present invention preferably contains50-99.8 wt. % of water-soluble carbohydrate selected from maltose,fructose, sucrose, lactose, glucose, galactose, trehalose, xylitol,sorbitol, erythritol, maltitol, mannitol, isomalt and combinationsthereof. More preferably, the water-soluble carbohydrate is selectedfrom lactose, mannitol, erythritol and combinations thereof. Even morepreferably, the water-soluble carbohydrate is selected from mannitol,erythritol and combinations thereof. Most preferably, the water-solublecarbohydrate is mannitol.

The water-soluble carbohydrate is preferably contained in the dosageunit in crystalline form.

According to another preferred embodiment, the dosage unit contains0.1-15 wt. %, more preferably 0.2-10 wt. % and most preferably 1-5 wt. %of a disintegrating agent selected from modified starches (e.g. sodiumsalt of carboxymethyl starch), crosslinked polyvinylpyrrolidone,crosslinked carmellose and combinations thereof.

The estetrol particles are present in the solid dosage unit of thepresent invention as a component of granules that additionally containone or more granulation excipients.

The dry estetrol-containing granules typically constitute 20-99.9 wt. %of the oral dosage unit. More preferably, these granules represent50-99.8 wt. %, most preferably 60-99.7 wt. % of the oral dosage unit.

Typically, the dry estetrol-containing granules that contain theestetrol particles have a volume median diameter of 100-4,000 μm, morepreferably of 150-1,000 μm and most preferably of 200-600 μm.

The dry estetrol-containing granules typically comprise 70-95 wt. % ofone or more granulation excipients and 5-30 wt. % of the estetrolcomponent. Even more preferably, these granules comprise 75-90 wt. % ofthe one or more granulation excipients and 10-25 wt. % of the estetrolcomponent.

Other granulation excipients that may suitably be incorporated into theestetrol-containing granules include water-soluble carbohydrate,diluents/fillers (e.g. calcium salts, microcrystalline cellulose),binders, disintegrating agents, mucoadhesive agents, flavouring,colouring, glidents, lubricants and combinations thereof.

The dry estetrol-containing granules preferably contain at least 20 wt.%, more preferably at least 35 wt. % and most preferably at least 45 wt.% of the water-soluble carbohydrate as defined herein before.

The dry estetrol-containing granules preferably contain at least 30%,more preferably at least 40% and most preferably at least 50% of thewater-soluble carbohydrate by weight of the one or more granulationexcipients.

The dry estetrol-containing granules typically contain 0-20 wt. % of thebinder as defined herein before. Even more preferably these granulescontain 0.1-15 wt. %, more preferably 0.2-10 wt. % of the binder.

In accordance with another preferred embodiment, the dryestetrol-containing granules comprise 0.1-20 wt. %, more preferably0.2-10 wt. % of a disintegrating agent as defined herein before.

Besides dry estetrol-containing granules, the solid dosage unit of thepresent invention may suitably contain 0.1-80 wt. %, more preferably0.2-50 wt. % and most preferably 0.3-40 wt. % of tabletting excipientsselected from lactose, mannitol, xylitol, microcrystalline cellulose,starch, croscarmellose sodium, polyvinyl pyrrolidone and combinationsthereof. According to one particularly preferred embodiment, thetabletting excipients comprises at least 50 wt. % mannitol. Inaccordance with another preferred embodiment, the tabletting excipientscomprise at least 50 wt. % lactose.

The solid dosage unit may contain one or more other pharmaceuticallyactive ingredients besides the estetrol component. Examples of suchother pharmaceutically active ingredients include steroid hormones. Thesolid dosage unit of the present invention preferably contains 0.05-10mg, more preferably 0.1-5 mg of one or more progestogens, preferably oneor more progestogens selected from progesterone, levonorgestrel,norgestimate, norethisterone, norethisteron-acetate (NETA),dydrogesterone, drospirenone, 3-beta-hydroxydesogestrel, 3-ketodesogestrel (=etonogestrel), 17-deacetyl norgestimate,19-norprogesterone, acetoxypregnenolone, allylestrenol, anagestone,chlormadinone, cyproterone, demegestone, desogestrel, dienogest,dihydrogesterone, dimethisterone, ethisterone, ethynodiol diacetate,flurogestone acetate, gastrinon, gestodene, gestrinone,hydroxymethylprogesterone, hydroxyprogesterone, lynestrenol(=lynoestrenol), medrogestone, medroxyprogesterone, megestrol,melengestrol, nestorone, nomegestrol, nomegestrol-acetate (NOMAC),norethindrone (=norethisterone), norethynodrel, norgestrel (includesd-norgestrel and dl-norgestrel), norgestrienone, normethisterone,progesterone, quingestanol,(17alpha)-17-hydroxy-11-methylene-19-norpregna-4,15-diene-20-yn-3-one,tibolone, trimegestone, algestone acetophenide, nestorone, promegestone,17-hydroxyprogesterone esters, 19-nor-17hydroxyprogesterone,17alpha-ethinyl-testosterone, 17alpha-ethinyl-19-nor-testosterone,d-17beta-acetoxy-13beta-ethyl-17alpha-ethinyl-gon-4-en-3-one oxime andprodrugs of these compounds. Preferably the one or more progestogensused in accordance with the present invention is selected from the groupconsisting of progesterone, desogestrel, etonogestrel, gestodene,dienogest, levonorgestrel, norgestimate, norethisterone,norethisteron-acetate (NETA), nomegestrol, nomegestrol-acetate (NOMAC),drospirenone, trimegestone, nestorone and dydrogesterone.

The solid dosage unit according to the present invention preferablycontains 0.05-100 mg, more preferably 0.1-50 mg of one or moreandrogens, preferably one or more androgens selected from testosterone,dehydroepiandrosterone (DHEA); DHEA-sulphate (DHEAS); testosteroneesters (e.g. testosterone undecanoate, testosterone propionate,testosterone phenylpropionate, testosterone isohexanoate, testosteroneenantate, testosterone bucanate, testosterone decanoate, testosteronebuciclate); methyltestosterone; mesterolon; stanozolol; androstenedione;dihydrotestosterone; androstanediol; metenolon; fluoxymesterone;oxymesterone; methandrostenolol; MENT and prodrugs of these compounds.Most preferably the one or more androgens are selected from the groupconsisting of testosterone, DHEA and MENT.

Another aspect of the present invention relates to the use of theaforementioned solid dosage unit in medical treatment, in female hormonereplacement therapy or in female contraception, said use comprisingsublingual, buccal or sublabial administration of the dosage unit.Examples of medical treatment in which the solid dosage unit of thepresent invention may suitably be used include treatment of osteoporosisand estrogen add-back treatment in endometriosis, breast cancer orprostate cancer. In accordance with a preferred embodiment, the soliddosage unit is used in female hormone replacement therapy or femalecontraception. Most preferably, the solid dosage is used in femalehormone replacement therapy, especially to treat vulvovaginal atrophyand/or vasomotor symptoms.

The use of the solid dosage unit in medical treatment, in female hormonereplacement therapy or in female contraception, typically comprisessublingual, buccal or sublabial administration of the dosage unit toprovide at least 0.1 mg, more preferably 0.5-100 mg and most preferably1-40 mg of the estetrol component.

To treat vulvovaginal atrophy the dosage unit is preferably administeredin an amount sufficient to provide at least 0.1 mg of the estetrolcomponent. More preferably, the administered dosage unit provides atleast 0.5 mg, most preferably at least 1 mg of the estetrol component.In the treatment of vulvovaginal atrophy the dosage unit is preferablyadministered in an amount that provides no more than 50 mg, morepreferably not more than 20 mg and most preferably not more than 10 mgof the estetrol component.

To treat vasomotor symptoms the dosage unit is preferably administeredin an amount sufficient to provide at least 0.2 mg of the estetrolcomponent. More preferably, the administered dosage unit provides atleast 1 mg, most preferably of at least 2 mg of the estetrol component.In the treatment of vasomotor symptoms the dosage unit is preferablyadministered in an amount that provides no more than 100 mg, morepreferably not more than 40 mg and most preferably not more than 20 mgof the estetrol component.

Typically, these uses of the solid dosage unit comprise once dailyadministration of the dosage unit during a period of at least 1 week,more preferably of at least 2 weeks. During these periods the soliddosage unit is preferably administered to provide a daily dose of atleast 0.05 mg, more preferably of 0.1-40 mg and most preferably of0.2-20 mg of the estetrol component.

To treat vulvovaginal atrophy the dosage unit is preferably administeredto provide a daily dose of at least 0.1 mg of the estetrol component.More preferably, the dosage unit is administered to provide a daily doseof 0.5-20 mg, most preferably of 1-10 mg of the estetrol component.

To treat vasomotor symptoms the dosage unit is preferably administeredto provide a daily dose of at least 0.2 mg of the estetrol component.More preferably, the dosage unit is administered to provide a daily doseof 1-40 mg, most preferably 2-20 mg of the estetrol component.

Yet another aspect of the invention relates to a process of preparing asolid dosage unit as described herein before, said process comprisingthe steps of:

-   -   providing estetrol particles containing at least 80 wt. % of an        estetrol component selected from estetrol, estetrol esters and        combinations thereof and having a volume median diameter of 2 μm        to 50 μm;    -   mixing the estetrol particles with one or more granulation        excipients to produce a granulation mixture;    -   mixing the granulation mixture with a granulation liquid to        produce estetrol-containing granules, said granulation liquid        containing at least 60 wt. % of liquid solvent;    -   removing liquid solvent from the estetrol-containing granules to        produce dry estetrol-containing granules;    -   optionally mixing the dry granules with one or more tabletting        excipients; and    -   forming the dry granules or the mixture of the dry granules and        the one or more tabletting excipients into a solid dosage unit.

In the present process the granulation mixture is preferably produced bycombining the estetrol particles with the one or more granulationexcipients in a weight ratio that is in the range of 1:2 to 1:1000, morepreferably in the range of 1:3 to 1:100 and most preferably in the rangeof 1:4 to 1:10.

The one or more granulation excipients used in the preparation of thegranulation mixture preferably include water-soluble carbohydrate asdefined herein before. Preferably, said water-soluble carbohydrateconstitutes at least 50 wt. %, more preferably at least 60 wt. % andmost preferably at least 80 wt. % of the one or more granulationexcipients.

The one or more granulation excipients of the granulation mixturepreferably include 0.1-20 wt. %, more preferably 0.15-10 wt. % and mostpreferably 0.2-5.0 wt. % of binder as defined herein before; allpercentage calculated by weight of the granulation mixture.

The one or more granulation excipients of the granulation mixture maysuitably include a disintegrating agent as defined herein before.Preferably, the disintegrating agent constitutes 0.1-20 wt. %, morepreferably 0.2-10 wt. % of the granulation mixture.

The estetrol-containing granules are preferably produced by mixing thegranulation mixture with the granulation liquid in a weight ratio thatis in the range of 0.5:1 to 20:1. Even more preferably, the granulationmixture and the granulation liquid are mixed in a weight ratio that isin the range of 0.8:1 to 12:1, even more preferably in the range of 1:1to 10:1 and most preferably of 1.5:1 to 5:1. The aforementioned weightratio is calculated on the basis of the total amount of granulationmixture and granulation liquid that is used in the preparation of thedry estetrol-containing granules.

The estetrol-containing granules are preferably produced by mixing thegranulation mixture with the granulation liquid in a high sheargranulator, a low shear granulator or a fluidized bed granulator. Mostpreferably, the granules are prepared in a low shear granulator.

The granulation liquid employed in the present process preferablycontains at least 60 wt. %, more preferably at least 80 wt. % and mostpreferably at least 90 wt. % of polar solvent selected from water,methanol, ethanol, iso-propanol, acetone and combinations thereof.

According to a particularly preferred embodiment, the granulation liquidcontains at least 60 wt. %, more preferably at least 80 wt. % and mostpreferably at least 90 wt. % of polar solvents selected from water,ethanol and combinations thereof. The polar solvent employed in thegranulation liquid preferably contains at least 80 wt. % water, morepreferably at least 90 wt. % water.

The granulation liquid employed in the present process may suitablycontain further excipients besides liquid solvent. Examples of suchfurther excipients include binders, disintegrating agents, mucoadhesiveagents, colouring, flavouring and combinations thereof.

Preferably, the granulation liquid contains 0.5-40 wt. %, morepreferably 1-25 wt. % and most preferably 2-20 wt. % of binder, saidbinder being selected from cellulose derivatives, starch and starchderivatives (e.g. pregelatinized starch), polyvinyl alcohol (PVA),polyvinylpyrrolidone (PVP), agar, gelatin, guar gum, gum Arabic,alginate, polyethylene glycol (PEG), glucose, sucrose, sorbitol andcombinations thereof. Preferably, the binder employed in the presentprocess is selected from cellulose derivatives, pregelatinized starch,polyvinylpyrrolidone and combinations thereof.

Examples of cellulose derivatives that may be employed in the dosageunit as binder include hydroxypropyl cellulose, hydroxyethyl cellulose,hydroxymethyl cellulose, hydroxypropylmethylcellulose, methylcellulose,ethylcellulose, carboxymethyl cellulose and combinations thereof.

In the present process liquid solvent is preferably removed after themixing of the granulation mixture with the granulation liquid has beencompleted. In a preferred embodiment reduced pressure is applied (e.g.less than 200 mbar) to facilitate the removal of liquid solvent duringproduction of the estetrol-containing granules. Typically, the liquidsolvent is removed at elevated temperature (e.g. >50° C.).

The dry estetrol-containing granules produced in the present processtypically have a volume median diameter in the range of 100-4,000 μm.More preferably, the volume median diameter of these granules is in therange of 200-1,000 μm, most preferably in the range of 200-600 μm.

Examples of the one or more tabletting excipients that are optionallycombined with the dry estetrol-containing granules before the forming ofthe solid dosage unit include lactose, mannitol, xylitol,microcrystalline cellulose, starch, croscarmellose sodium, polyvinylpyrrolidone and combinations thereof.

Preferably, in the present process the dry estetrol-containing granulesare mixed with the one or more tabletting excipients in a weight ratiothat is the range of 1:4 to 9:1, more preferably in the range of 1:2.5to 3:1 and most preferably of 1:1.5 to 1.5 to 1.

In the present process the solid dosage unit may suitably be formed bydirect compression or compression moulding. Most preferably, the soliddosage unit is formed by direct compression.

The solid dosage units obtained by the present method can be packaged indifferent ways. Preferably, the dosage units are packaged in a blisterpack containing at least 14 dosage units.

The invention is further illustrated by means of the followingnon-limiting examples.

EXAMPLES

Dissolution Test

The dissolution test described below can be used to study thedissolution behaviour of orodispersible dosage units.

Dissolution Apparatus

-   -   Paddle and basket dissolution tester VanKel VK 7010 or VK 7025,        autosampler VK 8000, 1000 mL dissolution vessels and porous        micron filters (35 pin)

Dissolution Medium

-   -   Transfer 9,000 ml of demineralised water into a volumetric flask        of 10,000 ml.    -   Add 68.05 g of KH₂PO₄ and 8.96 g NaOH and stir the solution        until everything is dissolved.    -   Mix the solution and adjust the pH to 6.8 with NaOH or        phosphoric acid, if necessary and make up to volume with        demineralised water.

Dissolution Procedure

-   -   Transfer 900 ml of Dissolution Medium into each vessel of the        paddle apparatus.    -   Assemble the apparatus, warm the medium to 37±0.5° C., and        remove the thermometer.    -   Place in each of the six vessels one tablet at the bottom before        starting the rotation of the paddles.    -   Start the rotation of the paddles immediately.    -   Use a stirring speed of 50 rpm.    -   Take samples of 5 ml from the dissolution vessels after 5, 10,        20, 30, 45, 60, 75 and 90 minutes for a complete dissolution        profile. Take the sample from a position midway between the        surface of the dissolution medium and the top of the paddle        blade and not less than 10 mm from the vessel wall. The removed        dissolution volume is not replaced by fresh dissolution medium.

Estetrol concentrations in the samples were determined by means of HPLCusing estetrol stock solutions as a reference.

Preparation of Mobile Phase (MP) Phosphate Buffer

-   -   Transfer 1.15 g of NH₄H₂PO₄ (10 mM) into a 1,000 ml of        demineralised water, dissolve it and adjust the pH to 3.0 with        phosphoric acid.

HPLC Apparatus

-   -   Alliance 2695 Separations module consisting of a quaternary        solvent delivery system, a variable volume injector, a        temperature controlled autosampler, column thermostat and        Photodiode array detector 2996 (all by Waters)    -   Analytical colunm: Symmetry C18, 3.9×150 mm, dp=5 μm (ex Waters)    -   Guard column: Security guard columg C18, 4×3 mm (Phenomenex)    -   Flow: 1.0 mL/min    -   Detection: UV @ 280 nm    -   Column temperature: 30° C.    -   Autosampler temperature: 10° C.    -   Injection volume: 100 μL    -   Run time: 12 min

Elution Gradient

Time (min) Acetonitrile (%) Phosphate buffer (%) 0 20 80 9 75 25 10 2080 12 20 80

The dissolution tests are conducted in triplicate.

Particle Size Measurements

Particle size distribution of estetrol monohydrate is performed using aMALVERN MASTERSIZER MICROPLUS laser particle size analyzer.

Preparation of Dispersion Medium:

-   -   Weigh 1 g of estetrol monohydrate and 1 g of sorbitan trioleate        into a flask.    -   Add 1 litre of n-hexane and mix for at least 1 hour at room        temperature    -   Filter through a 0.45 μm filter.

Sample Preparation:

-   -   Put 100 mg of sample in a 25 mL beaker.    -   Add some drops of dispersion medium.    -   Mix carefully with a glass rod to suspend well the powder.    -   Add 10 mL of dispersion medium.    -   Perform the analysis with the sample dispersion unit's speed at        3000-3500 rpm.

Analysis:

Particle size measurements are performed three times using the samedispersion. The final result is obtained by averaging the results of thethree determinations.

Example 1

A sublingual tablet is prepared by means of the procedure describedbelow.

A granulation mixture having the composition shown in Table 1 isprepared by dry blending of the ingredients.

TABLE 1 Ingredients Wt. % Milled estetrol ¹ 25 Mannitol 40 Lactose 35 ¹D(v; 0.5) = appr. 15 μm

A granulation liquid having the composition shown in Table 2 is preparedby dispersing the pregelatinized starch into the water

TABLE 2 Ingredients Wt. % Pregelatinized starch 2 Purified water 98

The granulation mixture is granulated in a high shear granulator bygradually adding the aqueous granulation liquid. The total amount ofgranulation liquid added amounts to 25% by weight of the granulationmixture.

The granulate so obtained is dried in a vacuum drying oven at 40° C. andsubsequently screened over a 500 μm sieve.

A tabletting mixture having the composition shown in Table 3 is preparedby mixing the dry granulate with the excipients for 15 minutes (exceptmagnesium stearate). Magnesium stearate is added and mixing is continuedfor an additional 5 minutes.

TABLE 3 Ingredients Wt. % Granulated estetrol 50 Lactose 10 Ludiflash ®² 38.5 Magnesium stearate 1.5 ² A mixture of mannitol (90 wt. %),crospovidone (5 wt. %) and polyvinyl acetate (5 wt. %)

The tabletting mixture is compressed into 80 mg round tablets with adiameter of 6.5 mm. The estetrol content of these tablets is 10 mg.

Example 2

A sublingual tablet is prepared by means of the procedure describedbelow.

A granulation mixture having the composition shown in Table 4 isprepared by dry blending of the ingredients.

TABLE 4 Ingredients Wt. % Milled estetrol ¹ 25 Lactose 75 ¹ D_((v; 0.5))= appr. 15 μm

A granulation liquid having the composition shown in Table 5 is preparedby dispersing the polyvinylpyrrolidone (PVP) into the water.

TABLE 5 Ingredients Wt. % PVP (polyvinylpyrrolidone) 3 Purified water 97

The granulation mixture is granulated in a low shear granulator bygradually adding the granulation liquid. The total amount of granulationliquid added amounts to 25% by weight of the granulation mixture.

The granulate so obtained is dried in the low shear granulator at 40° C.and is subsequently screened over a 500 μm sieve.

A tabletting mixture having the composition shown in Table 6 is preparedby mixing the dry granulate with the excipients for 15 minutes (exceptmagnesium stearate). Magnesium stearate is added and mixing is continuedfor an additional 5 minutes.

TABLE 6 Ingredients Wt. % Granulated estetrol 50 Mannitol 43.5Crospovidone 5 Magnesium stearate 1.5

The blend is compressed into 80 mg round tablets with diameter 6.5 mm.The estetrol content of these tablets is approximately 10 mg.

Example 3

A sublingual tablet is prepared using the procedure described below.

A granulation mixture having the composition shown in Table 7 isprepared by dry blending of the ingredients.

TABLE 7 Ingredients Wt. % Milled estetrol ¹ 25 Lactose 75 ¹ D_((v; 0.5))= appr. 15 μm

A granulation liquid having the composition shown in Table 8 is preparedby dispersing the hydroxypropyl cellulose (HPC) into the water.

TABLE 8 Ingredients Wt. % HPC (hydroxypropyl cellulose) 2 Purified water97

The granulation mixture is granulated in a fluid bed granulator bygradually adding the granulation liquid. The total amount of granulationliquid added amounts to 35% by weight of the granulation mixture.

The granulate so obtained is dried in the fluid bed granulator at 50° C.and subsequently screened over a 500 μm sieve.

A tabletting mixture having the composition shown in Table 9 is preparedby mixing the dry granulate with the excipients in Table 9 for 15minutes (except magnesium stearate). Magnesium stearate is added andmixing is continued for an additional 5 minutes.

TABLE 9 Ingredients Wt. % Granulated estetrol 50 Mannitol 43.5 Sodiumstarch glycolate 5 Magnesium stearate 1.5

The blend is compressed into 80 mg round tablets with diameter 6.5 mm.The estetrol content of these tablets is approximately 10 mg.

Example 4

Seven different sets of sublingual tablets (formulations A to G) wereprepared by means of the procedure described below and illustrated inFIG. 1.

The target amounts of estetrol per tablet were as follows: 100 μg forformulation A, 250 mg for formulation B, 7.5 mg for formulation C, 1 mgfor formulation D, and 10 mg for formulations E, F and G.

The target weights for the tablets were as follows: 30 mg forformulations A and C, 1000 mg for formulations B and D, and 80 mg forformulations E, F and G.

The estetrol was mixed with a part of the main diluent and screened overa 800 μm screen. All other excipients were also screened over a 800 μmscreen.

A binder solution of 10% PVP (polyvinylpyrrolidone) in demineralizedwater was prepared (the PVP concentration in the binder solution usedfor formulations B, C and F was 15%).

Granulation was started by adding the binder solution to the dry mixtureconsisting of the intragranular excipients (with a batchsize of ±100gram). A granulate was formed after 30 seconds of mixing, andsubsequently pure demineralized water was added until a suitablegranulate was formed (as detected visually, 1 minute of granulation intotal).

The granulate was dried overnight in a vacuum oven at 40° C. andsubsequently milled over a 800 μm screen. The mixture thus obtained wasmixed for 15 minutes with the extragranular excipients (except formagnesium stearate). Finally, magnesium stearate was added and mixed for3 minutes.

Compression was executed using a single punch machine equipped withproper punches (5 mm punch for 30 mg tablets (A and C), 6 mm for 80 mgtablets (E, F and G) and 15 mm for 1000 mg tablets (B and D)).

Disintegration time was quantified according to the known protocoldescribed in Ph. Eur. 2.9.1 (“Disintegration of tablets and capsules”),and in USP <701>(“Disintegration”) using water as the specified liquid.

Hardness was measured using the known protocol described in Ph. Eur.2.9.8 (“Resistance to crushing of tablets”).

The final formulations and corresponding tablet results can be found inTables 10 and 11 below.

No problems were detected during the experiments, flowability of theblend was good and no sticking was observed.

TABLE 10 details of the formulations in Wt. % Formulation # A B C D E FG Intragranular Milled Estetrol ¹ 0.33 24.92 25.00 0.10 12.49 12.4812.49 Mannitol 91.17 65.89 65.49 91.90 79.25 18.99 PVP (polyvinylpyr-2.00 2.99 3.00 2.00 2.01 1.46 rolidone) Pregelatinized starch 1.01Crospovidone 4.01 4.00 4.00 4.00 4.00 Lactose 17.51 36.04 Demineralizedwater 22 26 26 23 19 16 24 (per 100 gram granu- lation mixture)Extragranular Crospovidone 0.99 1.10 1.00 1.01 0.99 5.00 Lactose 10.01Ludiflash ®² 38.49 Mannitol 43.49 Magnesium stearate 1.49 1.10 1.50 0.991.25 1.50 1.52 ¹ D_((v; 0.5)) = 15 μm ²Containing mannitol (90 wt. %),crospovidone (5 wt. %) and polyvinyl acetate (5 wt. %)

TABLE 11 experimentally determined characteristics of the Tablets Test(average result of 6 samples) Disintegration time Hardness WeightFormulation # (min:sec) (N) (mg) A 0:39 14.17 28.2 B 1:44 85.85 1058.6 C1:05 28.46 30.1 D 0:40 66.74 1048.9 E 0:32 29.70 78.9 F 0:41 30.97 82.2G 0:33 22.69 78.1

It can be seen that all tablets were obtained with a final weight closeto their target weight and that the disintegration times, even for thelargest 1 g tablets, were very short, in accordance with the intendedsublingual, buccal or sublabial administration route for these tablets.

Finally, the hardness of all tablets was within a very acceptable range.

Example 5

A randomized, open-label, two-period, cross-over, pharmacokinetic studyis conducted to compare sublingual bioavailability of 10 mg estetroladministered in one 80 mg tablet (having the same composition as thetablets described in Example 4, Formulation E) with oral availability ofestetrol contained in a 83 mg tablet containing 10 mg estetrol. Thesetablets are administered sublingually and orally to healthy femalevolunteers under fasting conditions.

Ten healthy female subjects are selected on the basis of the followingcriteria: age of 45-65 years (inclusive), nonsmokers or past smokers (atleast 6 months before dosing), body-mass index (BMI)=18.5 to 30 kg/m²(inclusive at the time of the screening).

At the start of the first and the second period of the study, between07:00 am and 07:28 am, 5 subjects receive a single dose of thesublingual formulation of estetrol by administering one estetrol tablet(tablet weight 80 mg; 10 mg estetrol) and 5 subjects receive a singleoral dose of the oral estetrol formulation by administering one estetroltablet (tablet weight 83 mg; 10 mg estetrol), ingested together with 200ml water.

Subjects are required to fast for at least 10 hours prior to tabletadministration and for at least 4 hours after administration. Drinkingof water or beverages is not permitted within 1 hour before the drugadministration. Subjects receive 200 ml of water 1 hour prior to and 2hours after tablet administration. Subjects are free to drink water andfruit tea from 4 hours following the tablet administration. Standardizedmeals are provided 10.5 hours before and 4, 6, 9, and 13 hours aftertablet administration.

The sequence of events that occurs during the first and second period isshown in Table 12:

TABLE 12 Event First period Day 1 Confinement from 19:00 Day 2 Dosing,blood and urine sampling, confinement Day 3 Exit procedure, confinementtill 8 am Days 4-8 Return visits Days 9-13 Wash out Second period Day 14Confinement from 19:00 Day 15 Dosing, blood and urine sampling,confinement Day 16 Exit procedure, confinement till 8 am Days 17-21Return visits Days 22-26 Wash out Day 27 Administration of a progestinDay 28 Phone call, progestin withdrawal test check

The blood and urine sampling schedule used in this study is shown inTable 13.

TABLE 13 Blood Blood collection (4 ml) is performed prior toadministration sampling of the tablet (0), and subsequently 0:10, 0:15,0:20, 0:25, 0:30, 0:35, 0:40, 0:45, 0:50, 0:55, 1:00, 1:10, 1:20, 1:30,2, 3, 4, 6, 10, 16, 24, 48, 72, 96, 120, 144 hours after administration.Total number of blood collections in each period is 27. Urine Urinecollection is performed prior to administration of sampling the tabletand 2, 4, 8, 12, 24, 48, 72, 96, 120 and 144 hours after administration.Total number of urine collections in each period is 11.

The estetrol concentration in the collected blood samples is determinedby means of HPLC/MS/MS. The concentrations of glucuronided estetrol(D-ring) in the urine samples is also determined with the help ofHPLC/MS/MS.

Results of these analyses show that the bioavailability of sublinguallyadministered estetrol is comparable or even superior to orallyadministered estetrol. Furthermore, the data suggest that sublinguallyadministered estetrol has an earlier bioavailability compared to orallyadministered estetrol. Sublingual estetrol has less impact on a liverfunction parameter.

The invention claimed is:
 1. A process of making an orodispersible solidpharmaceutical dosage unit having a weight between 30 and 1,000 mg andcontaining at least 100 μg of an estetrol component selected from one ormore of estetrol and estetrol esters, wherein the dosage unit consistsof (i) 0.1-25 wt % estetrol particles, wherein the estetrol particlescomprise the estetrol component in an amount of at least 80 wt. % of theparticles and (ii) 75-99.9 wt. % of one or more pharmaceuticallyacceptable ingredients, the process comprising: providing estetrolparticles having a volume median diameter of from 2 μm to 50 μm andcomprising the estetrol component in an amount of at least 80 wt. % ofthe estetrol particles; mixing the estetrol particles with one or moregranulation excipients to produce a granulation mixture; mixing thegranulation mixture with a granulation liquid to produceestetrol-containing granules, wherein the granulation liquid comprises aliquid solvent in an amount of at least 60 wt. %; removing liquidsolvent from the estetrol-containing granules to produce dryestetrol-containing granules; optionally, mixing the dry granules withone or more tabletting excipients to produce a mixture; and forming thedry granules or the mixture into a solid dosage unit having a weightbetween 30 and 1,000 mg and containing at least 100 μg of the estetrolcomponent, wherein the estetrol particles make up 0.1-25 wt. % of thedosage unit.
 2. The process according to claim 1, wherein the estetrolparticles have a volume median diameter of 3-35 μm.
 3. The processaccording to claim 1, wherein the granulation mixture contains adisintegrating agent in an amount of 0.1-20 wt. % selected from one ormore of modified starches, crosslinked PVP, and crosslinked carmellose.4. The process according to claim 1, wherein the granulation mixture isproduced by combining the estetrol particles with the one or moregranulation excipients in a weight ratio that is in a range of from 1:4to 1:1,000.
 5. The process according to claim 1, wherein theestetrol-containing granules are produced by mixing the granulationmixture with the granulation liquid in a weight ratio that is in a rangeof from 0.5:1 to 20:1.
 6. The process according to claim 1, wherein theestetrol-containing granules are produced by mixing the granulationmixture with the granulation liquid in a high shear granulator, a lowshear granulator, or a fluidized bed granulator.
 7. The processaccording to claim 1, wherein the granulation liquid contains a polarsolvent in an amount of at least 60 wt. % selected from one or more ofwater, methanol, ethanol, isopropanol, and acetone.
 8. The processaccording to claim 1, wherein the granulation liquid contains a polarsolvent in an amount of at least 60 wt. % selected from one or more ofwater and ethanol.
 9. The process according to claim 7, wherein thepolar solvent contains at least 80 wt. % water.
 10. The processaccording to claim 1, wherein the granulation liquid contains a binderin an amount of 0.2-50 wt. % selected from one or more of cellulosederivatives, starch, starch derivatives, polyvinyl alcohol,polyvinylpyrrolidone, agar, gelatin, guar gum, gum Arabic, alginate,polyethylene glycol, glucose, sucrose, and sorbitol.
 11. The processaccording to claim 10, wherein the binder is selected from one or moreof cellulose derivatives, pregelatinized starch, andpolyvinylpyrrolidone.
 12. The process according to claim 10, wherein thebinder comprises a cellulose derivative selected from one or more ofhydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, methylcellulose,ethylcellulose, and carboxymethyl cellulose.
 13. The process accordingto claim 1, wherein the dry estetrol-containing granules have a volumemedian diameter in a range of from 100 to 4,000 μm.
 14. The processaccording to claim 1, wherein the one or more tabletting excipientscomprise one or more of lactose, mannitol, xylitol, microcrystallinecellulose, starch, croscarmellose sodium, and polyvinyl pyrrolidone. 15.The process according to claim 1, wherein the solid dosage unit isformed by direct compression or compression molding.
 16. The processaccording to claim 1, wherein the dosage unit has a weight between 40 mgand 500 mg.
 17. The process according to claim 1, wherein the dosageunit contains the estetrol component in an amount of 0.5-25 wt. % of thedosage unit.
 18. The process according to claim 1, wherein the dosageunit contains 0.3-100 mg of the estetrol component.
 19. The processaccording to claim 1, wherein the estetrol component is estetrol. 20.The process according to claim 1, wherein the dosage unit contains awater-soluble carbohydrate in an amount of 50-99.9 wt. %, selected fromone or more of maltose, fructose, sucrose, lactose, glucose, galactose,trehalose, xylitol, sorbitol, erythritol, maltitol, mannitol, andisomalt.
 21. The process according to claim 20, wherein the dosage unitcontains at least 20 wt. % mannitol.
 22. The process according to claim1, wherein the dosage unit contains a disintegrating agent in an amountof 0.1-20 wt. %, selected from one or more of modified starches,crosslinked polyvinylpyrrolidone, and crosslinked carmellose.